CA2173150C - Novel peptide derivatives - Google Patents
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- CA2173150C CA2173150C CA002173150A CA2173150A CA2173150C CA 2173150 C CA2173150 C CA 2173150C CA 002173150 A CA002173150 A CA 002173150A CA 2173150 A CA2173150 A CA 2173150A CA 2173150 C CA2173150 C CA 2173150C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/827—Proteins from mammals or birds
- Y10S530/829—Blood
- Y10S530/83—Plasma; serum
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
A peptide derivative represented by the following formula or a salt thereof <See formula I> wherein A and B each represent either of the following (a) and (b), (a) A represents a hydrogen atom, and B represents a phenyl group substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, or a heteroaryl group , (b) A represents -CONH-R1 , -CSNH-R1 , a hydroxymethyl group, a lower alkoxycarbonyl group or a carboxyl group, wherein, R1 represents a lower alkyl group or a heteroaryl group, and B represents a phenyl group optionally substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, has an antitumor activity stronger than that of dolastatin 10 , and is useful as an anticancer or antitumor agent.
Description
21731~~
DESCRI PT ION
NOVEL PEPTI DE DER IVATIV ES
Technical Field Thi s i nvent i on re 1 ates to a n oval pepti de derivative having an anti tumor activi ty, and, more detailedly, relates to a peptide derivative represented by the following formula or a salt thereof N H-~ H-C H 2-B
N I
N a ~ A
CHs NH I 0 OCHs ~N 0 C HaO C1"i3 C H3~ 0 (I) wherein A and B each represent either of the following (a) and (b), (a) A represents a hydrogen atom, and B
represents a phenyl group substituted with a hat ogen atom, hyd roxyl group, 1 ower al ky1 group or lower a1 koxy g roup, or a heteroa ry1 group , (b) A represents -CONH-R~ , -CSNH-R~ , a hydroxymethyl group, a lower alkoxycarbonyl group or a carboxyl group, wherein, R~~ repre-sents a lower alkyl group or a heteroaryl group, and B represents a phenyl group option-al l y substi tuted wi th a hat ogen atom, hyd roxyl group, lower alkyl group or lower alkoxy group .
Background Art Pepti des havi ng a cytos tati c acti vi ty and /or an antineoplasm activity have been isolated from marine _ mol l uscs, ses hare Do1 abe 1 1 a au ri cul a ri a and these pepti des are cal 1 ed do1 as tati ns 1 to 15 . Among t hem, 2 2173I~~
dolastatin 10 is a pentapeptide extracted from Dolabella auricul aria f rom the Indi an Ocean in1 1987 by. G. R.
Pettit, et a1. and having the following structural formula, and is sai d to be the strongest cytostatic substance presently known (see, G. R. Petti t, et a1 . , J .
Am. Chem. Soc . , 109 , 6883 ( 1987 ) and U. S. Patent No .
4,816,444).
i S
NH
- . N N ~ _ jo _ V
CHs ~ NH- i _ OCHs N ~ - OCH30CHj CHj~
[Dol astati n 10]
Further, recently, publ ication was made on the total synthesis of dolastatin 10 itself (see, U.S.
Patent No. 4, 978, 744) .
In this connection, the present inventors previously di sclosed certain dolastatin 10 derivatives ( see, W093/03054 Pamphl et ) .
The p resent i nven tors f ound t hat ce rtai n dolastatin 10 derivatives wherein the dolaphenine (which means an a-(thiazolyl)phenethylamino group) at the C-terminus of dolastatin i0 is substituted with another substituent have a~much stronger anti tumor activi ty than t hat of dot as tati n 10 .
Disclosure of Invention In the present description, - the term "lower"
means that the number of the carbon atoms of a group or compound to which this term is attached is 6 or less, preferably 4 or less.
- In the above formula (I), as the "lower alkyl group", there can, for example, be mentioned methyl , ethyl , n-propyl , isopropyl , n-butyl , i.sobutyl , sec-21?31~~
DESCRI PT ION
NOVEL PEPTI DE DER IVATIV ES
Technical Field Thi s i nvent i on re 1 ates to a n oval pepti de derivative having an anti tumor activi ty, and, more detailedly, relates to a peptide derivative represented by the following formula or a salt thereof N H-~ H-C H 2-B
N I
N a ~ A
CHs NH I 0 OCHs ~N 0 C HaO C1"i3 C H3~ 0 (I) wherein A and B each represent either of the following (a) and (b), (a) A represents a hydrogen atom, and B
represents a phenyl group substituted with a hat ogen atom, hyd roxyl group, 1 ower al ky1 group or lower a1 koxy g roup, or a heteroa ry1 group , (b) A represents -CONH-R~ , -CSNH-R~ , a hydroxymethyl group, a lower alkoxycarbonyl group or a carboxyl group, wherein, R~~ repre-sents a lower alkyl group or a heteroaryl group, and B represents a phenyl group option-al l y substi tuted wi th a hat ogen atom, hyd roxyl group, lower alkyl group or lower alkoxy group .
Background Art Pepti des havi ng a cytos tati c acti vi ty and /or an antineoplasm activity have been isolated from marine _ mol l uscs, ses hare Do1 abe 1 1 a au ri cul a ri a and these pepti des are cal 1 ed do1 as tati ns 1 to 15 . Among t hem, 2 2173I~~
dolastatin 10 is a pentapeptide extracted from Dolabella auricul aria f rom the Indi an Ocean in1 1987 by. G. R.
Pettit, et a1. and having the following structural formula, and is sai d to be the strongest cytostatic substance presently known (see, G. R. Petti t, et a1 . , J .
Am. Chem. Soc . , 109 , 6883 ( 1987 ) and U. S. Patent No .
4,816,444).
i S
NH
- . N N ~ _ jo _ V
CHs ~ NH- i _ OCHs N ~ - OCH30CHj CHj~
[Dol astati n 10]
Further, recently, publ ication was made on the total synthesis of dolastatin 10 itself (see, U.S.
Patent No. 4, 978, 744) .
In this connection, the present inventors previously di sclosed certain dolastatin 10 derivatives ( see, W093/03054 Pamphl et ) .
The p resent i nven tors f ound t hat ce rtai n dolastatin 10 derivatives wherein the dolaphenine (which means an a-(thiazolyl)phenethylamino group) at the C-terminus of dolastatin i0 is substituted with another substituent have a~much stronger anti tumor activi ty than t hat of dot as tati n 10 .
Disclosure of Invention In the present description, - the term "lower"
means that the number of the carbon atoms of a group or compound to which this term is attached is 6 or less, preferably 4 or less.
- In the above formula (I), as the "lower alkyl group", there can, for example, be mentioned methyl , ethyl , n-propyl , isopropyl , n-butyl , i.sobutyl , sec-21?31~~
butyl , tart-butyl , n-hexyl groups, etc. and as the "1 ower a1 koxy group", the re can , for exampl e, be men-tioned methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy groups, etc. Further, the "halogen atom" includes fluorine, chlorine, bromine and iodine atoms.
The "heteroaryl g roup" means an aromati c heterocyclic group contai ning hetero atoms) selected from 0, S and N, preferably, 5 or 6-membered heterocy-clic group containi rig 1 to 4 hetero atoms, such as thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl , thi adiazolyl , tetrazolyl , pyridyl , pyrimidinyl , triazi nyl groups,' etc.
The "phenyl group subst i tuted wi th a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy g roup" represented by the symbo 1 B i n cl udes a phe ny1 group substituted with one halogen atom, hydroxyl group, lower alkyl group or lower a7koxy group, and there can, for example, be mentioned 2-fluorophenyl, 2-chloro-p henyl , 2-bromophen yl , 3- f1 uoro phenyl , 3-i o dophen y1 , 4-chlorophenyl, 4-bromophenyl, 2-hydroxyphenyl, 2-methylphenyl, 4-ethylphenyl, 2-methoxyphenyl, 4-ethoxyphenyl groups, etc. Further, the "phenyl group optionally substituted wi th a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group" includes an unsubstituted phenyl group besides the above substi-tuted phenyl groups .
A group of prefer red compounds i n t he i nven-tion are compounds of the above formula (I) wherein A
represents a hydrogen atom and B represents a phenyl group substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, or a heteroaryl group, particularly compounds of the above formula (I) wherei n B rep resents a phenyl g coup s ubsti t uted wi th a hal ogen atom, hydroxyl group, 1 over al kyl g roup o r 1 owe r a1 koxy group; a thi enyl g roup; or a pyridyl group .
Another group of preferred compounds are compounds of the above formula (I) wherein A represents -CONH-R~ , -CS NH-R~ , a hyd roxyme thyl g coup, . a 1 owe r alkoxycarbonyl group or a carboxyl group, wherein R~
represents a lower alkyl group or a heteroaryl group, and B represents a phenyl group optionally substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, particularly compounds of the above formula (I) wherein A represents -CONH-R~ , -CSNH-R1 , a hydroxymethyl group, a lower al koxycarbonyl g coup o r a ca rboxyl group , wherei n R~ represents a 1 owe r alkyl group, a thiazolyl group or thiadiazolyl group, and B represents an unsubstituted phenyl group.
In the compounds of the above formula (I) of t he i nventi on , the carbon atoms to wh i ch an i sopropyl group, a sec-butyl group, a methoxy group and a methyl group bind respectively are asymmetric carbon atoms, and t herefo re, they can arbi t racy have an R- or S-con fi.gu-ration. All those compounds are included in the scope of the invention, but in view of pharmacological activi-ty, compounds having the same configuration as dolastatin 10 are preferred.
The peptide compounds of the above formula (I) can, further, exist as salts, preferably pharmaceutically acceptable salts, and as examples of such salts, there can be mentioned hydrochlorides, hydro-bromides, trifluoro acetates, p-toluenesulfonates, ace-tates, etc.
According to the invention, a peptide compound of the above formula (I) can be prepared by condensing the respective amino acids or peptide fragments, for axampl a , acco rdi ng to a l i qui d phase synthesi s me thod see, E . Schroder and K. Liibke, "The Peptides", vol ume 1, pages 76-136, 1965, published by Academic Press) known in the field of peptide chemistry.
For example, for avoiding racemization at the condensation reaction, it is preferred to conduct syn-thesis by condensing a tripeptide fragment of the fo1-~. 5 2I73T~' lowing formula (II) (II) N COOH
CH3~ NH
N ~ 0 C Ha0 C H3 C Hs~
with a fragment of the following formula (III) .
N N H i H C H2 B (III) H A
OCHs wherei n A and B a re as defi ned above.
Further, fo r synt hesi zi ng many compounds of the invention efficiently, it is preferred to conduct the synthesis by condensi ng a tetrapeptide fragment of the following formula (IV) OH
N
N ~ 0 ( IV) CHs, NH ~~ ~ OCH3 N~j 0 C H30 C Hs C H 3~ 0 with a fragment of~the following formula (V) H aN-C H-C H z-B
I ( wherei n A and B a re as defi ned above.
The condensation reacti on can be conducted, general 1 y, by treat i ng the fragments wi th a condensi ng agent, e.g. dicyclohexylcarbodi imide ,(DCC), Biphenyl phospho ryl az i de (DPPA) o r di et hy1 phosphorocyani date (DEPC), a so-called BOP reagent, or the like in an inert 21731~Q
s solvent such as, for example, chloroform, ethyl acetate, tetrahydrofuran (TH F), dimethylformamide (DMF) or aceto-nitrile, if necessary in the presence of an organic base such as, for example, triethylamine, N-methylmorpholine o r di i sopropyl ethyl ami ne (DIEA) .
The reaction temperature is usually -10°C to room temperature, preferably around 0°C . The ratios of the compound of the formula (III), the organic base and t he condensi n g agen t to t he compound of the formu 1 a ( I I ) are not strictly limited, but, usually, 'it is advanta-geous to use the compound of the formula (III) of at 1 east one mot e, preferabl y of the order of 1 .0 to 1 . 1 moles, the organic base of the order of 2 moles, and the condensing agent of the equimolar order, respectively per mole of the compound of the formula (II).
A compound of the formula (I) wherein A repre-sents a carboxyl group can also be prepared by alkali hydrolysis of the compound of the formula (I) wherein A
represents a lower alkoxycarbonyl group.
The i sol ati on and pu ri f i cati o n of t hus ob-tained peptid a compound of the formula (I) from the reaction mixture can be conducted by methods known per se, for example by recrystallization, ion exchange chromatography, gel filtration, high performance liquid chromatography, etc .
The compounds of the above formula (III) and (IV) used as starting materials in the above reaction are novel compounds not disclosed in prior literatures, and can easily be prepared by condensing amino acids, which are constituents thereof, according to a liquid phase synthesis method.
The peptide compounds of the formul a (I) of the invention have a higher antitumor activity than d of asta ti n 10 , and have a 1 arge therapeuti c i ndex , and are useful for treatment of acute myelocytic leukemia, acute 1 ymphocyti c 1 eukemi a, chroni c mel anoma, pul monary adenoca rci noma, neu robl as toma, put mon ary smal 1 cel 1 carcinoma, breast cancer, colon cancer, ovary cancer, b 1 adder cance r, etc .
The antitumor activity of the compounds c an be assayed as follows.
(1) - Assay of antitumor activity 0.1 m1 (106 cells/mouse) portions of mouse 1 eu kemi a P388 ce1 1 s we re -i mpl an ted i n t rape s i tones 1 1 y i nto 7-week-old CDF1 mice. A compound was intraperito-neatly admini stered thereinto on the fi rst day (the day after implantation) and the fifth day after implants-tion, and .the 1 i fe o~ dea-t-h o-f the mi ce .was observed fo r 60 days . From the resul is were cal cu 1 ated i ncreases i n 1 ife span (ILS, 96) according to the followi ng equation.
In the following equation, T means median survival days of the chemic a1 administration group, and C means median survival days of the control group.
T-C
ILS = x 100 C
The results are shown in the following Table.
Anti tumor act i vi ty i s shown as the re 1 ati ve rati o i n the case where the ILS of dot astati n 10 i s supposed to be 1 00 .
Example No. of compound Anti tumor activity dot astati n 10 100 The compounds of the invention, when used as a drug, can be used by formulating them, usually together with pharmaceutically acceptable carriers, into any dosage form of solid forms (e.g., tablets, hard capsules, soft capsules, granules, powders, fi ne granules, pills, t roches , etc. ) , semi-sot i d forms (e. g . , supposi to ri es, ,.....
8 2r ~ 3 I s~
ointments, etc.) and liquid forms (e.g., injections, emulsions, suspensi ons, 1 otions , sprays, etc. ) . As nontoxi c addi tives usable in the above formulations, there can, for example, ba mentioned starches, gelatin, g 1 ucose , 1 act ose, f ructos a , ma1 tose , magnes i um ca rbon-ate, talc, magnesium stearate, methyl cellul ose, carboxymethyl cellul ose or sat is thereof, gum arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl esters, syrups, ethanol , propyl ene gl ycol , vase7 i ne , carbowax, glycerol, sodium chloride, sodium sulfite, sodium phos-phate, citric acid, etc. The drug can also contain another therapeutically effecti ve drug.
The content of the compound of the invention in the drug varies depending on the dosage form, but it i s gene ral l y prefer red that the drug contai ns the com-pound at a concentration of 0.1 to 50 wt 96 in the case of solid and semi-solid forms, and at a concentration of 0 .05 to 10 wt 96 i n the case of 1 i qui d form.
The dose of the compound of t he i nventi on can widely be varied depending on the kind of warm-blooded animals including human beings as a subject, administra-tion routes, the seriousness of symptoms, the diagnoses of doctors, etc. , but can generally be on the order of 0.01 to 50 mg/kg per day. However, i t is of course possi bl a to admi ni s ter the compound i n an amount smal 1 a r t han th a 1 owe r 1 i mi t of t he abo ve ran ge o r i n an amoun t 1 arger than t he upper 1 imi t the reof i n acco rdance wi th the seriousness of symptom of the patient and the diag-nosis of the doctor as mentioned above. The above dose can be admi ni stered once a day or i n di vi ded seve ral portions per day.
Exampl es The invention is further described below according to Referential Examples and Examples.
As for the structure of compounds correspond-21731~~
ing to compound numbers used in Referential Examples and Examples, please refer to the followi ng Flow Sheets 1 and 2. Therein, But represents a tert-butyl group, Boc a tart-butoxy carbonyl group, Bz1 a benzyl group, Me a methyl group, B a phenyl group substituted with a halo gen atom, hydroxyl group, lower alkyl group or lower a1 koxy group, or a heteroaryl g roup, and A -CONH-R~ , -CSNH-R~ , a hydroxymethyl group, a lower al koxycarbonyl g roup o r a ca rboxyl group , wherei n R~ represents a 1 owe r alkyl group or a heteroaryl group.
217 31~~
..
F1 ow Shee t 1 ~CHO ~C00B21 .) 8oc Referential Example 1 - ~ ~~C008z1 Boc [0 H Cad 2 N C 0 0 But _ Referential M e' N H I 0 M a Exarr~le 2 N I 0 Me Mew 0 Cc~r~pOUnd 1 N C 0 0 Bz 1 H~ Boc 0 M a C°~w-~d 3 - I H+
Referential Fxarr~le 3 N~C 0 0 Bzl N I I 0 M a C~~d 4 Mew I~ H ~~ ~MeO
Me~N ~ 0 Me N ~ ~ Me B
M e' H ~ I M a . H 2 N~
M a N ~ 0 M a C~und 4' .
F~casnples 1 - 14 , B
N H~
N. .
N Me0 M \_ NH ~ I OMeO
N 11 0 M a Ca~ound 5 M e~ O
21731~~
F1 ow Shee t 2 BocNH # COOH
Referential Exa~rple 4 BocN H * A
Ca~und 6 N COON
N ' ~ M a H+
Me\ NH I I OMeO
~N I 0 M a M a 0 Car~ound 4 ' Examples 15 - 25 i N ~H * A
N ~ II
N ~ 0 Me0 Me\ N H , I 0 Me0 N 0 Me M e~ ~ Ca~ound 7 .
~173~~~
Referential Example 1 P repara ti on o f compound 2 30 ml of a tet rah yd rofu ran - n-hexa ne ( 1 . 1 ) solution of 23.8 % lithium diisopropylamide (LDA, 66.4 mmoles) is gradually poured into 40 ml of anhydrous tetrahydrofuran and er stirring at -20° in an atmosphere of nitrogen, the mixture is cooled to -78~ , and 9.84 g (60 rtlmoles) of benzyl propionate is added dropwise over a period of 30 minutes. 5 minutes later, a solution of 7.96 g (40 mmoles) of Boc-prolinal in 40 ml of tetra-hydrofuran is added dropwise at the same temperature over a period of 1 hour. The mixture is stirred at the same temperature for 15 minutes, 150 m1 of ice-cooled 1N-hydrochloric acid is added, and the mixture is warmed t o room tempe ratu re . The mi xtu re i s ext rac ted wi th a thyl acetate , the ethyl acetat a 1 aye r i s washed wi th water and dried, the solvent is distilled off under reduced pressure, and the remai ning oily matter i s puri fi ed by s i 1 i ca gel f1 ash ch romatography usi ng ethyl acetate - n-hexane (1 . 5) as an eluent to obtain the desi red compound 2 as cot orless of 1y matter . 3.86 g (26.6 %).
~ a ]p 2 T -28 . 4° (c - 0.82, MeOH) ~ H-NM R ( CDC 13 , a ) 1 . 30 ( 3H , d , J=7 . OHz ) , 1 . 45 (9H, s), 1.6-2.1 (m), 2.61 (1H, quintet, J=7.OHz), 3.0-3.6 (m), 3.7-4.1 (m), 5.13 (2H, s), 7.34 (5H, s) Referential Example 2 Preparation of compound 3 730 mg (2.01 mmoles) of compound 2 obtained in Referential Example 1 is dissolved in 10 ml of di-methyl f ormami de, 0. 7 ml ( 1 1 . 22 mmol es ) of methyl i odi de is gourd therein under stirring, and 0.16 g (4.00 mmoles) of sodium hydride (60 % in mineral oil) is added t herei n . Sti rri ng i s con ti nued at 0° for 1 hour, i ce water is added, and the mixture is extracted with ethyl acetate - ben zene ( 4 . 1 ) . The organ i c 1 ayer i s washed ,m.
2I731:~~
with 5 %. potassium hydrogen su1 fate, saturated aqueous sodium bicarbonate, 5 % sodium thiosulfate and saturated sat i ne i n thi s orde r, and dri ed . The resul taut c rude p roduct i s pu ri fi ed by si 1 i ca gel f1 ash chromatog raphy using ethyl acetate - n-hexane (1 . 10) as an eluent to obtain the desired compound 3 as colorless oily matter.
The "heteroaryl g roup" means an aromati c heterocyclic group contai ning hetero atoms) selected from 0, S and N, preferably, 5 or 6-membered heterocy-clic group containi rig 1 to 4 hetero atoms, such as thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl , thi adiazolyl , tetrazolyl , pyridyl , pyrimidinyl , triazi nyl groups,' etc.
The "phenyl group subst i tuted wi th a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy g roup" represented by the symbo 1 B i n cl udes a phe ny1 group substituted with one halogen atom, hydroxyl group, lower alkyl group or lower a7koxy group, and there can, for example, be mentioned 2-fluorophenyl, 2-chloro-p henyl , 2-bromophen yl , 3- f1 uoro phenyl , 3-i o dophen y1 , 4-chlorophenyl, 4-bromophenyl, 2-hydroxyphenyl, 2-methylphenyl, 4-ethylphenyl, 2-methoxyphenyl, 4-ethoxyphenyl groups, etc. Further, the "phenyl group optionally substituted wi th a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group" includes an unsubstituted phenyl group besides the above substi-tuted phenyl groups .
A group of prefer red compounds i n t he i nven-tion are compounds of the above formula (I) wherein A
represents a hydrogen atom and B represents a phenyl group substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, or a heteroaryl group, particularly compounds of the above formula (I) wherei n B rep resents a phenyl g coup s ubsti t uted wi th a hal ogen atom, hydroxyl group, 1 over al kyl g roup o r 1 owe r a1 koxy group; a thi enyl g roup; or a pyridyl group .
Another group of preferred compounds are compounds of the above formula (I) wherein A represents -CONH-R~ , -CS NH-R~ , a hyd roxyme thyl g coup, . a 1 owe r alkoxycarbonyl group or a carboxyl group, wherein R~
represents a lower alkyl group or a heteroaryl group, and B represents a phenyl group optionally substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, particularly compounds of the above formula (I) wherein A represents -CONH-R~ , -CSNH-R1 , a hydroxymethyl group, a lower al koxycarbonyl g coup o r a ca rboxyl group , wherei n R~ represents a 1 owe r alkyl group, a thiazolyl group or thiadiazolyl group, and B represents an unsubstituted phenyl group.
In the compounds of the above formula (I) of t he i nventi on , the carbon atoms to wh i ch an i sopropyl group, a sec-butyl group, a methoxy group and a methyl group bind respectively are asymmetric carbon atoms, and t herefo re, they can arbi t racy have an R- or S-con fi.gu-ration. All those compounds are included in the scope of the invention, but in view of pharmacological activi-ty, compounds having the same configuration as dolastatin 10 are preferred.
The peptide compounds of the above formula (I) can, further, exist as salts, preferably pharmaceutically acceptable salts, and as examples of such salts, there can be mentioned hydrochlorides, hydro-bromides, trifluoro acetates, p-toluenesulfonates, ace-tates, etc.
According to the invention, a peptide compound of the above formula (I) can be prepared by condensing the respective amino acids or peptide fragments, for axampl a , acco rdi ng to a l i qui d phase synthesi s me thod see, E . Schroder and K. Liibke, "The Peptides", vol ume 1, pages 76-136, 1965, published by Academic Press) known in the field of peptide chemistry.
For example, for avoiding racemization at the condensation reaction, it is preferred to conduct syn-thesis by condensing a tripeptide fragment of the fo1-~. 5 2I73T~' lowing formula (II) (II) N COOH
CH3~ NH
N ~ 0 C Ha0 C H3 C Hs~
with a fragment of the following formula (III) .
N N H i H C H2 B (III) H A
OCHs wherei n A and B a re as defi ned above.
Further, fo r synt hesi zi ng many compounds of the invention efficiently, it is preferred to conduct the synthesis by condensi ng a tetrapeptide fragment of the following formula (IV) OH
N
N ~ 0 ( IV) CHs, NH ~~ ~ OCH3 N~j 0 C H30 C Hs C H 3~ 0 with a fragment of~the following formula (V) H aN-C H-C H z-B
I ( wherei n A and B a re as defi ned above.
The condensation reacti on can be conducted, general 1 y, by treat i ng the fragments wi th a condensi ng agent, e.g. dicyclohexylcarbodi imide ,(DCC), Biphenyl phospho ryl az i de (DPPA) o r di et hy1 phosphorocyani date (DEPC), a so-called BOP reagent, or the like in an inert 21731~Q
s solvent such as, for example, chloroform, ethyl acetate, tetrahydrofuran (TH F), dimethylformamide (DMF) or aceto-nitrile, if necessary in the presence of an organic base such as, for example, triethylamine, N-methylmorpholine o r di i sopropyl ethyl ami ne (DIEA) .
The reaction temperature is usually -10°C to room temperature, preferably around 0°C . The ratios of the compound of the formula (III), the organic base and t he condensi n g agen t to t he compound of the formu 1 a ( I I ) are not strictly limited, but, usually, 'it is advanta-geous to use the compound of the formula (III) of at 1 east one mot e, preferabl y of the order of 1 .0 to 1 . 1 moles, the organic base of the order of 2 moles, and the condensing agent of the equimolar order, respectively per mole of the compound of the formula (II).
A compound of the formula (I) wherein A repre-sents a carboxyl group can also be prepared by alkali hydrolysis of the compound of the formula (I) wherein A
represents a lower alkoxycarbonyl group.
The i sol ati on and pu ri f i cati o n of t hus ob-tained peptid a compound of the formula (I) from the reaction mixture can be conducted by methods known per se, for example by recrystallization, ion exchange chromatography, gel filtration, high performance liquid chromatography, etc .
The compounds of the above formula (III) and (IV) used as starting materials in the above reaction are novel compounds not disclosed in prior literatures, and can easily be prepared by condensing amino acids, which are constituents thereof, according to a liquid phase synthesis method.
The peptide compounds of the formul a (I) of the invention have a higher antitumor activity than d of asta ti n 10 , and have a 1 arge therapeuti c i ndex , and are useful for treatment of acute myelocytic leukemia, acute 1 ymphocyti c 1 eukemi a, chroni c mel anoma, pul monary adenoca rci noma, neu robl as toma, put mon ary smal 1 cel 1 carcinoma, breast cancer, colon cancer, ovary cancer, b 1 adder cance r, etc .
The antitumor activity of the compounds c an be assayed as follows.
(1) - Assay of antitumor activity 0.1 m1 (106 cells/mouse) portions of mouse 1 eu kemi a P388 ce1 1 s we re -i mpl an ted i n t rape s i tones 1 1 y i nto 7-week-old CDF1 mice. A compound was intraperito-neatly admini stered thereinto on the fi rst day (the day after implantation) and the fifth day after implants-tion, and .the 1 i fe o~ dea-t-h o-f the mi ce .was observed fo r 60 days . From the resul is were cal cu 1 ated i ncreases i n 1 ife span (ILS, 96) according to the followi ng equation.
In the following equation, T means median survival days of the chemic a1 administration group, and C means median survival days of the control group.
T-C
ILS = x 100 C
The results are shown in the following Table.
Anti tumor act i vi ty i s shown as the re 1 ati ve rati o i n the case where the ILS of dot astati n 10 i s supposed to be 1 00 .
Example No. of compound Anti tumor activity dot astati n 10 100 The compounds of the invention, when used as a drug, can be used by formulating them, usually together with pharmaceutically acceptable carriers, into any dosage form of solid forms (e.g., tablets, hard capsules, soft capsules, granules, powders, fi ne granules, pills, t roches , etc. ) , semi-sot i d forms (e. g . , supposi to ri es, ,.....
8 2r ~ 3 I s~
ointments, etc.) and liquid forms (e.g., injections, emulsions, suspensi ons, 1 otions , sprays, etc. ) . As nontoxi c addi tives usable in the above formulations, there can, for example, ba mentioned starches, gelatin, g 1 ucose , 1 act ose, f ructos a , ma1 tose , magnes i um ca rbon-ate, talc, magnesium stearate, methyl cellul ose, carboxymethyl cellul ose or sat is thereof, gum arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl esters, syrups, ethanol , propyl ene gl ycol , vase7 i ne , carbowax, glycerol, sodium chloride, sodium sulfite, sodium phos-phate, citric acid, etc. The drug can also contain another therapeutically effecti ve drug.
The content of the compound of the invention in the drug varies depending on the dosage form, but it i s gene ral l y prefer red that the drug contai ns the com-pound at a concentration of 0.1 to 50 wt 96 in the case of solid and semi-solid forms, and at a concentration of 0 .05 to 10 wt 96 i n the case of 1 i qui d form.
The dose of the compound of t he i nventi on can widely be varied depending on the kind of warm-blooded animals including human beings as a subject, administra-tion routes, the seriousness of symptoms, the diagnoses of doctors, etc. , but can generally be on the order of 0.01 to 50 mg/kg per day. However, i t is of course possi bl a to admi ni s ter the compound i n an amount smal 1 a r t han th a 1 owe r 1 i mi t of t he abo ve ran ge o r i n an amoun t 1 arger than t he upper 1 imi t the reof i n acco rdance wi th the seriousness of symptom of the patient and the diag-nosis of the doctor as mentioned above. The above dose can be admi ni stered once a day or i n di vi ded seve ral portions per day.
Exampl es The invention is further described below according to Referential Examples and Examples.
As for the structure of compounds correspond-21731~~
ing to compound numbers used in Referential Examples and Examples, please refer to the followi ng Flow Sheets 1 and 2. Therein, But represents a tert-butyl group, Boc a tart-butoxy carbonyl group, Bz1 a benzyl group, Me a methyl group, B a phenyl group substituted with a halo gen atom, hydroxyl group, lower alkyl group or lower a1 koxy group, or a heteroaryl g roup, and A -CONH-R~ , -CSNH-R~ , a hydroxymethyl group, a lower al koxycarbonyl g roup o r a ca rboxyl group , wherei n R~ represents a 1 owe r alkyl group or a heteroaryl group.
217 31~~
..
F1 ow Shee t 1 ~CHO ~C00B21 .) 8oc Referential Example 1 - ~ ~~C008z1 Boc [0 H Cad 2 N C 0 0 But _ Referential M e' N H I 0 M a Exarr~le 2 N I 0 Me Mew 0 Cc~r~pOUnd 1 N C 0 0 Bz 1 H~ Boc 0 M a C°~w-~d 3 - I H+
Referential Fxarr~le 3 N~C 0 0 Bzl N I I 0 M a C~~d 4 Mew I~ H ~~ ~MeO
Me~N ~ 0 Me N ~ ~ Me B
M e' H ~ I M a . H 2 N~
M a N ~ 0 M a C~und 4' .
F~casnples 1 - 14 , B
N H~
N. .
N Me0 M \_ NH ~ I OMeO
N 11 0 M a Ca~ound 5 M e~ O
21731~~
F1 ow Shee t 2 BocNH # COOH
Referential Exa~rple 4 BocN H * A
Ca~und 6 N COON
N ' ~ M a H+
Me\ NH I I OMeO
~N I 0 M a M a 0 Car~ound 4 ' Examples 15 - 25 i N ~H * A
N ~ II
N ~ 0 Me0 Me\ N H , I 0 Me0 N 0 Me M e~ ~ Ca~ound 7 .
~173~~~
Referential Example 1 P repara ti on o f compound 2 30 ml of a tet rah yd rofu ran - n-hexa ne ( 1 . 1 ) solution of 23.8 % lithium diisopropylamide (LDA, 66.4 mmoles) is gradually poured into 40 ml of anhydrous tetrahydrofuran and er stirring at -20° in an atmosphere of nitrogen, the mixture is cooled to -78~ , and 9.84 g (60 rtlmoles) of benzyl propionate is added dropwise over a period of 30 minutes. 5 minutes later, a solution of 7.96 g (40 mmoles) of Boc-prolinal in 40 ml of tetra-hydrofuran is added dropwise at the same temperature over a period of 1 hour. The mixture is stirred at the same temperature for 15 minutes, 150 m1 of ice-cooled 1N-hydrochloric acid is added, and the mixture is warmed t o room tempe ratu re . The mi xtu re i s ext rac ted wi th a thyl acetate , the ethyl acetat a 1 aye r i s washed wi th water and dried, the solvent is distilled off under reduced pressure, and the remai ning oily matter i s puri fi ed by s i 1 i ca gel f1 ash ch romatography usi ng ethyl acetate - n-hexane (1 . 5) as an eluent to obtain the desi red compound 2 as cot orless of 1y matter . 3.86 g (26.6 %).
~ a ]p 2 T -28 . 4° (c - 0.82, MeOH) ~ H-NM R ( CDC 13 , a ) 1 . 30 ( 3H , d , J=7 . OHz ) , 1 . 45 (9H, s), 1.6-2.1 (m), 2.61 (1H, quintet, J=7.OHz), 3.0-3.6 (m), 3.7-4.1 (m), 5.13 (2H, s), 7.34 (5H, s) Referential Example 2 Preparation of compound 3 730 mg (2.01 mmoles) of compound 2 obtained in Referential Example 1 is dissolved in 10 ml of di-methyl f ormami de, 0. 7 ml ( 1 1 . 22 mmol es ) of methyl i odi de is gourd therein under stirring, and 0.16 g (4.00 mmoles) of sodium hydride (60 % in mineral oil) is added t herei n . Sti rri ng i s con ti nued at 0° for 1 hour, i ce water is added, and the mixture is extracted with ethyl acetate - ben zene ( 4 . 1 ) . The organ i c 1 ayer i s washed ,m.
2I731:~~
with 5 %. potassium hydrogen su1 fate, saturated aqueous sodium bicarbonate, 5 % sodium thiosulfate and saturated sat i ne i n thi s orde r, and dri ed . The resul taut c rude p roduct i s pu ri fi ed by si 1 i ca gel f1 ash chromatog raphy using ethyl acetate - n-hexane (1 . 10) as an eluent to obtain the desired compound 3 as colorless oily matter.
5 30 mg ( 72 . 5 %) .
[ a ]p 2 ~ -25 . 7° (c - 0.389, Me OH) ~ H-NMR (CDC13 , a ) 1 .26 (3H, d, J=6 .BHz) , 1 .45 (9H, s), 1.65-2.1 (m), 2.56 (1H, quintet, J=7.OHz), 3.0-4 .0 (m) , 3.38 (3H, s) , 5. 14 (2H , s) , 7.34 ( 5H, s) Referential Example 3 Preparation of compound 4 (a) 1 m1 o f concept rat ed hyd rochl o ri c ac i d i s added to 97.1 mg (0.2 mmole) of compound 1 (known com-pound) under ice cooling, and the mixture is stirred at 0° for 1 hour and evaporated to dryness under reduced p ressu re . Th a resi due i s di sso 1 ved i n 2 ml of dimethylformamide, 0.15 m1 of triethylamine is added dropwise at 0~ , and the mixture is again evaporated to d ryness under reduced pressure.
(b) On the other hand, 76 mg (0.2 mmole) of compound 3 obtained in Referential Example 2 is dis-s o1 ved i n 0 . 5 m1 of ethyl aceta te, 2 . 0 m1 o f 2N-h yd rope n c hl on d e/ethy 1 acet ate i s added under i ce cool i ng , and the mixture i s brought to room temperature, sti rred for 1 .5 hours, evaporated to dryness under reduced pressure and then dried.
The products obtained in (a) and (b) are combined and dissolved in 0.8 m1 of dimethylformamide, 34.3 mg (1.1 equivalents) of DE PC is added, the mixture i s ice-cooled , 56 p1 (2 equival ents) of tri ethylamine i s added, and st i rri ng i s conti nued unde r i ce cool i ng for 1 hour and then at room temperatu re ove rni ght . The so1-vent is evaporated under reduced pressure, the residue i s dissolved in dichloromethane, and the solution is washed. with saturated aqueous sodium bicarbonate and saturated sat ine and dried. The resultant crude product i s purl fied by sili ca gel flash chromatography using dichloromethane - methanol (20 . 1) as an eluent, and t hen by Sephadex*LH-20 ch romatography usi ng n-hexane -dichloromethane - methanol (2 . 7.5 . 2.5) as an eluent to obtain the desired compound 4 as an amorphous solid.
1 1 7 mg (85.0 96) .
( Q )p 2 6 -44 .0° (c - 0.80, MeOH) ~ H-NM R ( CDC 13 , b ) 0 . 7-1 . 5 ( m ) , 1 . 2 7 ( 3H , d , J=7. OHz ) , 1 . 5-2 . 25 (m) , 2 .25-2. 9 (m) , 3. 01 (3H, s ) , 3.29 ( 3H, s) , 3:35 (3H, s) , 3. 8-4.3 (m) , 4 .5-5.0 (m) , 5. 13 ( 2H, s) , 7.34 (5H, s) Referen ti al Exampl a 4-A
P repara ti on o f compound 6-A
( i n compound 6, A = CONH-Et, * - S) 1 . 33 g ( 5 mmol es ) of Bo c-phen yl al an i ne i s .
dissolved in 20 ml of tetrahydrofuran, and while the solution is stirred at -15~ , 0.56 m1 (5 mmoles) of N-methylmorphol i ne and then 0.67 ml ( 5 mmol es) of i sobu-tyl chl oroformate are added. After sti rring the mixture at -15° for 5 minutes, 0. 64 g (2 equi valents) of aqueous 70 96 ethylami ne so1 ution is added, and sti rring i s continued at -15° for 15 minutes and then at room tem-perature for 1.5 hours. The reaction solution is con-centrated under reduced pressure, the residue is dis-solved in ethyl acetate, the solution is washed with i ce-cooled 2N-hydrochlori c acid and saturated aqueous sodium bicarbonate and dried, the solvent is distilled -off, and the residue is crystallized from ethyl acetate-ether-n-hexane to obtai n the desi red compound 6-A as needle crystals. 1 .12 g (76.7 96) .
Mel ti ng poi nt 123-4~ .
~ H-NM R ( CDC 13 , a ) 0 . 99 ( 3H , t , J=7 . 3Hz ) , 1 . 41 (9H, s) , 2.9-3.2 (m), 3.22 (2H, q, J=7.3Hz) , 4.25 (1H, dd, J=14.3Hz, J=7.5Hz), 5.04 (1H, br. d) 5.61 (1H, br.
*Trade-mark '.-.
s ) , 7.25 (5H, s) ', Referen ti a1 Exampl a 4-B
Prepafation of compound 6-B
( i n compound 6, A = CONH-Et, * - R) 5 The desi red compound 6-B is obtained from BOC-D-phenyl a1 ani ne i n a1 1 the same manner as i n Refer-ential Exampl a 4-A.
Referen ti al Exampl a 4-C
Preparation of compound 6-C
( i n compound 6, A = .CpNH-~ , * = S ) N
133 mg (0.5 mmole) of Boc-phenylalanine and 50 mg (0.5 mmole) of 2-aminothiazole are dissolved i n 1 ml of dimethylformamide, and while the solution is stirred a t 0~ , 86 mg ( 1 equ i val en t ) of DEPC a nd 70 p1 ( 1 equi v-alent) of triethylamine are added. After stirring is continued at 0° for 3 hours and then at room temperature overnight, the mixture is evaporated to dryness under reduced pressure, the residue i s dissolved in dichloro methane , and the so 1 uti on i s washed wi th 10 96 ci t ri c aci d an d satu rated aqueou s sodi um bi c arbona to and d ri ed .
The crude product is purified by preparative TLC using ethyl acetate - n-hexane (3 . 4) as a developing solvent to obtain the desired compound 6-C as sand-like crys t al s . 128 mg (73 . 6 96) . Me1 ti n g poi n t 158- 160 .
[a ]p25 -11.0° (c - 0.2, CHC13) ~ H-NM R ( CDC 13 , a ) 1 . 41 ( 9H , s ) , 3 . 0-3 . 3 (2H, m), 4.5-4.8 (1H, m), 5.0-5.2 (1H, br. d), 7.23 (5H, m) , 7.26 (2H, dd, J=41 .3Hz , J=3. 7Hz) Referential Example 4-D
P repara ti on o f comp ound 6-D
( i n compound 6, A = N~N , * = S) The d esi red compo and 6-D i s o btai ned f rom BOC-phenylalanine and 2-amino-1,3,4-thiadiazole in all CONH--~~
t he same manner as i n Ref erenti al Exampl a 4-C.
[a ]p2T +34.1° (c - 0.960, Me OH) ~ H-NM R ( CDC 13 , a ) 1 . 28 ( 9H , s ) , 3 . 0-3 . 3 (2H, m), 4.6-4.9 (1H, m), 6.27 (1H, d, J=7.3Hz}, 7.26 (5H, s) , 8.84 (1H, s), 13.5 (1H, br. s) Referen ti a1 Exampl a 4-E
Preparation of compound 6-E
(in compound 6, A = CSNH-Et, * - S) 0.217 g (0.745 mmole) of compound 6-A obtained in Referential Exam ple 4- A and 151 mg (0.5 equivalent) of Lawesson reagent are dissolved in 5 ml of benzene, and the solution is refluxed with heating for 45 min-a tes . The re acti on sot a t i on i s evapo rated to d ry ness under reduced pressure, and the residue is puri fi ed by preparative TLC usi ng dichloromethane - methanol (40 1) as a developing solvent to obtain the desired thioamide (compound 6-E) as a yellow waxy solid. 0.230 g (quan ti tati ve) .
~ H-NMR (CDC13 , a ) 1 .01 (3H, t, J=7.3Hz), 1 .41 (9H, s), 3.0-3.2 (2H, m), 3.3-3.7 (2H, m), 4.48 (1H, dd, J=14.5Hz, J=7 .9Hz) , 5.25-5.55 ( 1H, br . d) , 7.24 ( 5H, s) Fv~mnl0 1 P repara ti on o f compound 5-A
( i n compound 5, B =
(a) 400 mg (0.58 mmol a ) of compound 4 ob-tained in Referential Example 3 is dissolved in 6 ml of t-butanol - water ( 9 . 1 ) , 80 mg of 5 96 pal 1 adi um-carbon is added, and the solution is stirred under a stream of hydrogen for 5 hours. The catalyst is filtered and washed, and the fil trate and the washings are evaporated to dryness under reduced pressure and dried to obtain compound 4' , a carboxyl is acid, as a colorl ess gl asst' solid. 337 mg (quantitative).
(b) 35 mg (60 pmoles) of the carboxylic acid obtained in (a) and 14 mg (1.5 equivalents) of p-chlorophenethylamine are dissolved in 0.5 ml of dimethylformamide, and under ice cooling and stirring, 12.4 mg (1.2 equivalents) of DE PC and 16 p1 (1.88 equiv-alents) of triethylamine are added, and stirring is continued at 0° for at least 3 hours and then overnight allowing the ice to melt. The reaction solution is concentrated under reduced pressure, the residue is dissolved in dichloromethane, and the solution is washed with saturated aqueous sodium bicarbonate and saturated saline and dried. The resultant crude product is puri-fied by preparative TLC using dichloromethane - methanol ( 10 . 1 ) as a devel opi ng so1 ven t and then Sephadex LH-20 chromatography using n-hexane - dichloromethane - metha-nol (2 . 7.5 . 2.5) as an e1 uen t to obtai n the desi red compoun d 5-A as amo rphous powde r . 35 . 2 mg ( 79 . 6 96) .
[u ]828 -32.9° (c - 0.292, Me OH) ~ H-NM R ( CDC 13 , a ) 0 . 7- 1 . 1 ( m ) , 1 . 2 2 ( 3H , d , J=7.OHz ) , 2.26 (6H, s) , 3 .03 (3H, s) , 3.31 (3H, s ) , 3.36 (3H, s), 3.7-4.2 (m), 4.79 (1H, dd, J=9.2Hz, 6.6Hz), 6.86 (1H, br. d), 7.1-7.3 (4H, m) r Examples 2 to 15 The following compounds are obtained by react-i ng compound 4' wi t h the corres pondi n g phenethyl ami ne derivative in the same manner as in Example 1.
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x w ' ~-- 217310 Exampl a 16 P repara ti on o f compound 7-A
( i n compound 7, A = CONH-~ . * = S) _ N
70 mg (0 . 2 mmol e) of compound 6-C o btai ned i n Referen ti a1 Exampl a 4-C i s di ssol ved i n 1 m1 of 50 96 t ri f1 uo roacet i c aci d-di ch 1 orome thane at 0~ , and t he solution is brought to room temperature, stirred for 3 hours and evaporated uncle r reduced pressure . The resi-due is washed thoroughly with ether and dried under reduced pressure.
The above compound and 88 mg (0.15 mmole) of compound 4' obtained in (a) of Example 1 are dissolved in 1.5 ml of dimethylformamide, and under ice cooling and sti rri ng, 30 mg (0. 184 mmol e) of DEPC and 41 mg (0.406 mmole) of triethyl amine are added. Sti rri ng is continued at 0° for 3 hours and then at room temperature overnight, the reaction solution is evaporated under re-duced pressure, the residue is dissolved in dichloro-methane, and the solution is washed with saturated aqueous sodium bicarbonate and saturated saline and d ried. The resul tant product i s puri fied by preparative T LC usi ng di c hl oromethane - met hanol ( 10 . 1 ) as a d evel op i ng so 1 vent to obt ai n th a desi red compound 7-A as whi to powder. 86.5 mg (69.6 96) .
[a ]p28 -26.1° (c - 0.3185, MeOH) ~ H-NMR (CDC13 , 3 ) 0.7-1 :3 (m), 1 .1 1 (3H, d, J=6.6Hz ) , 2.98 (3H, s) , 2 .99 (3H, s) , 3.34 (6H, s ) , 3.5-4.2 (m), 4.5-5.1 (m), 7.23 (5H, s), 7.41 (2H, dd, J =56 . 5H z , J=4 . OHz ) Examples 17 to 24 Compounds 6-A, 6-B, 6-D and 6-E obtained in Referen ti a1 Exampl es 4-A, 4-B, 4-D and 4-E are deprotected respect i vel y accord i ng to Examp 1 a 16, and then reacted with compound 4' to obtain the desired 2I'~31~0 ~,~., compounds 7-B, 7-C, 7-D and 7-E. Likewise, by re action of L- or D-phenylalanine methyl ester hydrochloride or phenylalanine ethyl ester or phenylalaninol with com-pound 4' , the corresponding compounds 7-F, 7-G, ?-H and 7-I are obtai ned . The re sul is are shown i n the f of 1 ow-i ng Tab 1 a .
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Example 25 Preparation of compound 7-J
( i n compound 7, A = COOH, * = S ) 38.1 mg (50 pmoles) of compound 7-F obtained i n Exampl a 21 i s di ssol ved i n 0 . 5 ml of met hanol , 55 p1 (55 pmoles) of 1N-sodium hydroxide is added, and the mixture is stirred at room temperature for 3 hours. The mixture is ice-cool ed, 55 p1 of 1N-hydrochl oric acid is added, the mixture is evaporated to dryness under re-duced pressure, and the tetrahydrofuran-sol uble part of the residue i s puri fied by Sephadex LH-20 chromatography using n-hexane - di chloromethane - methanol (2 . 7.5 2 .5) as an e1 uent to obtai n powder of the desi red com-pound 7-J. 37.4 mg (100 96) .
[ a ]0 3 0 -33 .4° (c - 0.3265, MeOH) ~ H-NM R ( CDC 13 , b ) 0 . 6- 1 . 3 ( m ) , 1 . 5 -2 . 2 ( m ) , 2 . 6-2 . 8 ( 6H , m ) , 3 . 07 ( 3H , s ) , 3 . 33 ( 3H , s ) , 3 . 38 (3H, s) , 3.6-4.2 (m), 4.5-4.9 (m), 7.21 (5H, s) Exampl a 26 P repara ti on o f compound 7-K
( i n compound 7, A = COOH, * = R) Compound 7-K i s obtai ned from compound 7-G i n all the same manner as in Example 25.
[ a ] 0 2 9 -63 . 4° ( c - 0 . 3 30 , Me OH ) ~ H-NMR (CDC13 , b ) 0.7-1 .4 (m), 1 .5-2.3 (m), 2 .71 (6H, br. s) , 3 .04 (3H, s) , 3.32 (3H, s ) , 3.37 (3H, s) , 4.6-5.0 (m), 7.22 (5H, s)
[ a ]p 2 ~ -25 . 7° (c - 0.389, Me OH) ~ H-NMR (CDC13 , a ) 1 .26 (3H, d, J=6 .BHz) , 1 .45 (9H, s), 1.65-2.1 (m), 2.56 (1H, quintet, J=7.OHz), 3.0-4 .0 (m) , 3.38 (3H, s) , 5. 14 (2H , s) , 7.34 ( 5H, s) Referential Example 3 Preparation of compound 4 (a) 1 m1 o f concept rat ed hyd rochl o ri c ac i d i s added to 97.1 mg (0.2 mmole) of compound 1 (known com-pound) under ice cooling, and the mixture is stirred at 0° for 1 hour and evaporated to dryness under reduced p ressu re . Th a resi due i s di sso 1 ved i n 2 ml of dimethylformamide, 0.15 m1 of triethylamine is added dropwise at 0~ , and the mixture is again evaporated to d ryness under reduced pressure.
(b) On the other hand, 76 mg (0.2 mmole) of compound 3 obtained in Referential Example 2 is dis-s o1 ved i n 0 . 5 m1 of ethyl aceta te, 2 . 0 m1 o f 2N-h yd rope n c hl on d e/ethy 1 acet ate i s added under i ce cool i ng , and the mixture i s brought to room temperature, sti rred for 1 .5 hours, evaporated to dryness under reduced pressure and then dried.
The products obtained in (a) and (b) are combined and dissolved in 0.8 m1 of dimethylformamide, 34.3 mg (1.1 equivalents) of DE PC is added, the mixture i s ice-cooled , 56 p1 (2 equival ents) of tri ethylamine i s added, and st i rri ng i s conti nued unde r i ce cool i ng for 1 hour and then at room temperatu re ove rni ght . The so1-vent is evaporated under reduced pressure, the residue i s dissolved in dichloromethane, and the solution is washed. with saturated aqueous sodium bicarbonate and saturated sat ine and dried. The resultant crude product i s purl fied by sili ca gel flash chromatography using dichloromethane - methanol (20 . 1) as an eluent, and t hen by Sephadex*LH-20 ch romatography usi ng n-hexane -dichloromethane - methanol (2 . 7.5 . 2.5) as an eluent to obtain the desired compound 4 as an amorphous solid.
1 1 7 mg (85.0 96) .
( Q )p 2 6 -44 .0° (c - 0.80, MeOH) ~ H-NM R ( CDC 13 , b ) 0 . 7-1 . 5 ( m ) , 1 . 2 7 ( 3H , d , J=7. OHz ) , 1 . 5-2 . 25 (m) , 2 .25-2. 9 (m) , 3. 01 (3H, s ) , 3.29 ( 3H, s) , 3:35 (3H, s) , 3. 8-4.3 (m) , 4 .5-5.0 (m) , 5. 13 ( 2H, s) , 7.34 (5H, s) Referen ti al Exampl a 4-A
P repara ti on o f compound 6-A
( i n compound 6, A = CONH-Et, * - S) 1 . 33 g ( 5 mmol es ) of Bo c-phen yl al an i ne i s .
dissolved in 20 ml of tetrahydrofuran, and while the solution is stirred at -15~ , 0.56 m1 (5 mmoles) of N-methylmorphol i ne and then 0.67 ml ( 5 mmol es) of i sobu-tyl chl oroformate are added. After sti rring the mixture at -15° for 5 minutes, 0. 64 g (2 equi valents) of aqueous 70 96 ethylami ne so1 ution is added, and sti rring i s continued at -15° for 15 minutes and then at room tem-perature for 1.5 hours. The reaction solution is con-centrated under reduced pressure, the residue is dis-solved in ethyl acetate, the solution is washed with i ce-cooled 2N-hydrochlori c acid and saturated aqueous sodium bicarbonate and dried, the solvent is distilled -off, and the residue is crystallized from ethyl acetate-ether-n-hexane to obtai n the desi red compound 6-A as needle crystals. 1 .12 g (76.7 96) .
Mel ti ng poi nt 123-4~ .
~ H-NM R ( CDC 13 , a ) 0 . 99 ( 3H , t , J=7 . 3Hz ) , 1 . 41 (9H, s) , 2.9-3.2 (m), 3.22 (2H, q, J=7.3Hz) , 4.25 (1H, dd, J=14.3Hz, J=7.5Hz), 5.04 (1H, br. d) 5.61 (1H, br.
*Trade-mark '.-.
s ) , 7.25 (5H, s) ', Referen ti a1 Exampl a 4-B
Prepafation of compound 6-B
( i n compound 6, A = CONH-Et, * - R) 5 The desi red compound 6-B is obtained from BOC-D-phenyl a1 ani ne i n a1 1 the same manner as i n Refer-ential Exampl a 4-A.
Referen ti al Exampl a 4-C
Preparation of compound 6-C
( i n compound 6, A = .CpNH-~ , * = S ) N
133 mg (0.5 mmole) of Boc-phenylalanine and 50 mg (0.5 mmole) of 2-aminothiazole are dissolved i n 1 ml of dimethylformamide, and while the solution is stirred a t 0~ , 86 mg ( 1 equ i val en t ) of DEPC a nd 70 p1 ( 1 equi v-alent) of triethylamine are added. After stirring is continued at 0° for 3 hours and then at room temperature overnight, the mixture is evaporated to dryness under reduced pressure, the residue i s dissolved in dichloro methane , and the so 1 uti on i s washed wi th 10 96 ci t ri c aci d an d satu rated aqueou s sodi um bi c arbona to and d ri ed .
The crude product is purified by preparative TLC using ethyl acetate - n-hexane (3 . 4) as a developing solvent to obtain the desired compound 6-C as sand-like crys t al s . 128 mg (73 . 6 96) . Me1 ti n g poi n t 158- 160 .
[a ]p25 -11.0° (c - 0.2, CHC13) ~ H-NM R ( CDC 13 , a ) 1 . 41 ( 9H , s ) , 3 . 0-3 . 3 (2H, m), 4.5-4.8 (1H, m), 5.0-5.2 (1H, br. d), 7.23 (5H, m) , 7.26 (2H, dd, J=41 .3Hz , J=3. 7Hz) Referential Example 4-D
P repara ti on o f comp ound 6-D
( i n compound 6, A = N~N , * = S) The d esi red compo and 6-D i s o btai ned f rom BOC-phenylalanine and 2-amino-1,3,4-thiadiazole in all CONH--~~
t he same manner as i n Ref erenti al Exampl a 4-C.
[a ]p2T +34.1° (c - 0.960, Me OH) ~ H-NM R ( CDC 13 , a ) 1 . 28 ( 9H , s ) , 3 . 0-3 . 3 (2H, m), 4.6-4.9 (1H, m), 6.27 (1H, d, J=7.3Hz}, 7.26 (5H, s) , 8.84 (1H, s), 13.5 (1H, br. s) Referen ti a1 Exampl a 4-E
Preparation of compound 6-E
(in compound 6, A = CSNH-Et, * - S) 0.217 g (0.745 mmole) of compound 6-A obtained in Referential Exam ple 4- A and 151 mg (0.5 equivalent) of Lawesson reagent are dissolved in 5 ml of benzene, and the solution is refluxed with heating for 45 min-a tes . The re acti on sot a t i on i s evapo rated to d ry ness under reduced pressure, and the residue is puri fi ed by preparative TLC usi ng dichloromethane - methanol (40 1) as a developing solvent to obtain the desired thioamide (compound 6-E) as a yellow waxy solid. 0.230 g (quan ti tati ve) .
~ H-NMR (CDC13 , a ) 1 .01 (3H, t, J=7.3Hz), 1 .41 (9H, s), 3.0-3.2 (2H, m), 3.3-3.7 (2H, m), 4.48 (1H, dd, J=14.5Hz, J=7 .9Hz) , 5.25-5.55 ( 1H, br . d) , 7.24 ( 5H, s) Fv~mnl0 1 P repara ti on o f compound 5-A
( i n compound 5, B =
(a) 400 mg (0.58 mmol a ) of compound 4 ob-tained in Referential Example 3 is dissolved in 6 ml of t-butanol - water ( 9 . 1 ) , 80 mg of 5 96 pal 1 adi um-carbon is added, and the solution is stirred under a stream of hydrogen for 5 hours. The catalyst is filtered and washed, and the fil trate and the washings are evaporated to dryness under reduced pressure and dried to obtain compound 4' , a carboxyl is acid, as a colorl ess gl asst' solid. 337 mg (quantitative).
(b) 35 mg (60 pmoles) of the carboxylic acid obtained in (a) and 14 mg (1.5 equivalents) of p-chlorophenethylamine are dissolved in 0.5 ml of dimethylformamide, and under ice cooling and stirring, 12.4 mg (1.2 equivalents) of DE PC and 16 p1 (1.88 equiv-alents) of triethylamine are added, and stirring is continued at 0° for at least 3 hours and then overnight allowing the ice to melt. The reaction solution is concentrated under reduced pressure, the residue is dissolved in dichloromethane, and the solution is washed with saturated aqueous sodium bicarbonate and saturated saline and dried. The resultant crude product is puri-fied by preparative TLC using dichloromethane - methanol ( 10 . 1 ) as a devel opi ng so1 ven t and then Sephadex LH-20 chromatography using n-hexane - dichloromethane - metha-nol (2 . 7.5 . 2.5) as an e1 uen t to obtai n the desi red compoun d 5-A as amo rphous powde r . 35 . 2 mg ( 79 . 6 96) .
[u ]828 -32.9° (c - 0.292, Me OH) ~ H-NM R ( CDC 13 , a ) 0 . 7- 1 . 1 ( m ) , 1 . 2 2 ( 3H , d , J=7.OHz ) , 2.26 (6H, s) , 3 .03 (3H, s) , 3.31 (3H, s ) , 3.36 (3H, s), 3.7-4.2 (m), 4.79 (1H, dd, J=9.2Hz, 6.6Hz), 6.86 (1H, br. d), 7.1-7.3 (4H, m) r Examples 2 to 15 The following compounds are obtained by react-i ng compound 4' wi t h the corres pondi n g phenethyl ami ne derivative in the same manner as in Example 1.
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a v U v v v~ ~ z z o o i i o ~r' 'n U
ri C1, ~ .n E
x w ' ~-- 217310 Exampl a 16 P repara ti on o f compound 7-A
( i n compound 7, A = CONH-~ . * = S) _ N
70 mg (0 . 2 mmol e) of compound 6-C o btai ned i n Referen ti a1 Exampl a 4-C i s di ssol ved i n 1 m1 of 50 96 t ri f1 uo roacet i c aci d-di ch 1 orome thane at 0~ , and t he solution is brought to room temperature, stirred for 3 hours and evaporated uncle r reduced pressure . The resi-due is washed thoroughly with ether and dried under reduced pressure.
The above compound and 88 mg (0.15 mmole) of compound 4' obtained in (a) of Example 1 are dissolved in 1.5 ml of dimethylformamide, and under ice cooling and sti rri ng, 30 mg (0. 184 mmol e) of DEPC and 41 mg (0.406 mmole) of triethyl amine are added. Sti rri ng is continued at 0° for 3 hours and then at room temperature overnight, the reaction solution is evaporated under re-duced pressure, the residue is dissolved in dichloro-methane, and the solution is washed with saturated aqueous sodium bicarbonate and saturated saline and d ried. The resul tant product i s puri fied by preparative T LC usi ng di c hl oromethane - met hanol ( 10 . 1 ) as a d evel op i ng so 1 vent to obt ai n th a desi red compound 7-A as whi to powder. 86.5 mg (69.6 96) .
[a ]p28 -26.1° (c - 0.3185, MeOH) ~ H-NMR (CDC13 , 3 ) 0.7-1 :3 (m), 1 .1 1 (3H, d, J=6.6Hz ) , 2.98 (3H, s) , 2 .99 (3H, s) , 3.34 (6H, s ) , 3.5-4.2 (m), 4.5-5.1 (m), 7.23 (5H, s), 7.41 (2H, dd, J =56 . 5H z , J=4 . OHz ) Examples 17 to 24 Compounds 6-A, 6-B, 6-D and 6-E obtained in Referen ti a1 Exampl es 4-A, 4-B, 4-D and 4-E are deprotected respect i vel y accord i ng to Examp 1 a 16, and then reacted with compound 4' to obtain the desired 2I'~31~0 ~,~., compounds 7-B, 7-C, 7-D and 7-E. Likewise, by re action of L- or D-phenylalanine methyl ester hydrochloride or phenylalanine ethyl ester or phenylalaninol with com-pound 4' , the corresponding compounds 7-F, 7-G, ?-H and 7-I are obtai ned . The re sul is are shown i n the f of 1 ow-i ng Tab 1 a .
I I
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Example 25 Preparation of compound 7-J
( i n compound 7, A = COOH, * = S ) 38.1 mg (50 pmoles) of compound 7-F obtained i n Exampl a 21 i s di ssol ved i n 0 . 5 ml of met hanol , 55 p1 (55 pmoles) of 1N-sodium hydroxide is added, and the mixture is stirred at room temperature for 3 hours. The mixture is ice-cool ed, 55 p1 of 1N-hydrochl oric acid is added, the mixture is evaporated to dryness under re-duced pressure, and the tetrahydrofuran-sol uble part of the residue i s puri fied by Sephadex LH-20 chromatography using n-hexane - di chloromethane - methanol (2 . 7.5 2 .5) as an e1 uent to obtai n powder of the desi red com-pound 7-J. 37.4 mg (100 96) .
[ a ]0 3 0 -33 .4° (c - 0.3265, MeOH) ~ H-NM R ( CDC 13 , b ) 0 . 6- 1 . 3 ( m ) , 1 . 5 -2 . 2 ( m ) , 2 . 6-2 . 8 ( 6H , m ) , 3 . 07 ( 3H , s ) , 3 . 33 ( 3H , s ) , 3 . 38 (3H, s) , 3.6-4.2 (m), 4.5-4.9 (m), 7.21 (5H, s) Exampl a 26 P repara ti on o f compound 7-K
( i n compound 7, A = COOH, * = R) Compound 7-K i s obtai ned from compound 7-G i n all the same manner as in Example 25.
[ a ] 0 2 9 -63 . 4° ( c - 0 . 3 30 , Me OH ) ~ H-NMR (CDC13 , b ) 0.7-1 .4 (m), 1 .5-2.3 (m), 2 .71 (6H, br. s) , 3 .04 (3H, s) , 3.32 (3H, s ) , 3.37 (3H, s) , 4.6-5.0 (m), 7.22 (5H, s)
Claims (6)
1. A peptide derivative represented by the following formula:
or a salt thereof, wherein A represents a hydrogen atom, and B represents a phenyl group substituted with an o-fluoro group or hydroxyl group, or, a heteroaryl group.
or a salt thereof, wherein A represents a hydrogen atom, and B represents a phenyl group substituted with an o-fluoro group or hydroxyl group, or, a heteroaryl group.
2. The peptide derivative or salt according to claim 1, wherein B represents a heteroaryl group selected from the group consisting of thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl and triazinyl groups.
3. The peptide derivative or salt according to claim 1, wherein B represents a thienyl or pyridyl group.
4. The peptide derivative or salt according to claim 1, wherein B represents a phenyl group substituted with an o-fluoro group or hydroxyl group.
5. The peptide or salt according to any one of claims 1 to 4, wherein the peptide has the formula:
6. An antitumor drug, which comprises:
the peptide derivative as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
the peptide derivative as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26964293 | 1993-10-01 | ||
| JP269642/1993 | 1993-10-01 | ||
| PCT/JP1994/001560 WO1995009864A1 (en) | 1993-10-01 | 1994-09-22 | Novel peptide derivative |
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|---|---|
| CA2173150A1 CA2173150A1 (en) | 1995-04-13 |
| CA2173150C true CA2173150C (en) | 2004-11-30 |
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| CA002173150A Expired - Fee Related CA2173150C (en) | 1993-10-01 | 1994-09-22 | Novel peptide derivatives |
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| US (2) | US5767237A (en) |
| EP (1) | EP0731106B1 (en) |
| JP (1) | JP3469580B2 (en) |
| KR (1) | KR100332254B1 (en) |
| AT (1) | ATE282630T1 (en) |
| AU (1) | AU689131B2 (en) |
| CA (1) | CA2173150C (en) |
| DE (1) | DE69434136T2 (en) |
| ES (1) | ES2233928T3 (en) |
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| US4816444A (en) * | 1987-07-10 | 1989-03-28 | Arizona Board Of Regents, Arizona State University | Cell growth inhibitory substance |
| US4978744A (en) * | 1989-01-27 | 1990-12-18 | Arizona Board Of Regents | Synthesis of dolastatin 10 |
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| US5635483A (en) * | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
| US5410024A (en) * | 1993-01-21 | 1995-04-25 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide amides |
| US5780588A (en) * | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
| EP0731106B1 (en) * | 1993-10-01 | 2004-11-17 | Teikoku Hormone Mfg. Co., Ltd. | Dolastatin derivatives |
| CN1113066C (en) * | 1995-04-21 | 2003-07-02 | 帝国脏器制药株式会社 | Novel Peptide Derivatives |
| US5939527A (en) * | 1996-07-30 | 1999-08-17 | Basf Aktiengesellschaft | Tetrapeptides as antitumor agents |
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1994
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- 1994-09-22 JP JP51071795A patent/JP3469580B2/en not_active Expired - Fee Related
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| ATE282630T1 (en) | 2004-12-15 |
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| EP0731106A4 (en) | 1998-12-23 |
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